ATLANTAMouthwash containing a modified virus that kills
cells lacking p53 (a common deletion in many cancerous and
precancerous lesions) may prevent development of invasive squamous
cell head and neck cancers in smokers, researchers reported at the
annual meeting of the American Society of Clinical Oncology.
The ONYX-015 agent is an attenuated adenovirus that is unable to
productively infect normal human cells, but can replicate in and lyse
cells that do not have normal p53 function.
The viral agent is being tested in advanced solid tumors, but a
poster presented by Charles W. Rudin, MD, PhD, and his colleagues at
the University of Chicago suggested that it may be even more
effective at preventing premalignant lesions from developing into
One of the normal cellular responses to adenovirus infection is to
turn on p53 expression, if p53 is present. Normal cells infected with
ONYX-015 would thus activate p53. Cells unable to activate p53, such
as precancerous cells that have lost p53 function, are unable to
defuse the virus and are destroyed.
Dr. Rudin reported preliminary results of a phase I/II trial of
ONYX-015 given as a mouthwash for the treatment of clinically evident
oropharyngeal dysplastic lesions. The mouthwash containing ONYX-015
was administered daily for 5 days, with treatments repeated every 4
weeks. For each patient, doses were escalated from a starting dose of
Patients with dysplastic lesions of the oropharynx, including
erythroplakia and leukoplakia, are at high risk for the development
of invasive squamous cell carcinoma of the head and neck, Dr.
Rudin said. An estimated 45% to 50% of these dysplastic lesions
carry inactivating mutations of the p53 gene, and a proportion of the
remaining dysplastic lesions may have functional defects in p53
This trial is designed to include 20 patients. Dr. Rudin reported
data on the first five. The first patient, with a history of invasive
squamous cell carcinoma, had severe dysplasia. Two others had
mild-to-moderate dysplasia or focal dysplasia, and two had
The first patient was a 28-year-old woman with a carcinoma of the
tongue that had been resected via a hemiglossectomy. She had
recurrence at the surgical margin with a 1-cm plaque of leukoplakia
that, on biopsy, was severely dysplastic. The lesion was p53-abnormal
through the full thickness of the mucosa.
This was a worrisome, genetically abnormal lesion in a patient
who previously had cancer. This patient was at extremely high risk
for cancer recurrence, Dr. Rudin said.
The patient was treated with the ONYX-015 mouthwash daily for 5 days
and was biopsied again the next week. The surgeon [who was
scheduled to re-biopsy the 1-cm plaque] called me and said,
Im supposed to biopsy this lesion, but its
gone, Dr. Rudin said. We told her to biopsy the
mucosa where the plaque had been, and it showed only mild dysplasia
with minimal abnormal cells after only one cycle of the
The patient has been treated with 11 cycles so far and has had a
complete resolution of all evidence of dysplasia. There is no
abnormality evident in the mucosa, and the tissue is now p53 normal
by immunohistochemistry. We think we have taken a woman who was
at extremely high risk for cancer recurrence and may have
significantly reduced that risk, he said.
Dr. Rudin cautioned that whether this benefit would be sustained if
treatment were halted is yet to be determined. The patient will
receive one more cycle of treatment, then will be monitored for 6
months for signs of recurrence.
Dr. Rudin said that no adverse effects have been noted up to the
final dose level of 1010 pfu/day in patients treated daily for 1 week
Use of the ONYX-015 mouthwash will be expanded in a multi-institution
trial in oral dysplasia, he said.
The most striking thing about the study is that the entire oral
surface was exposed to the adenovirus, said David H. Kirn, MD, vice
president for clinical research at Onyx Pharmaceuticals, which
developed the mouthwash. The normal cells were entirely
unaffected, but the dysplastic lesions resolved in the two patients
who were p53 abnormal, Dr. Kirn said. This study is the
result of 20 years of basic research on what is essentially a common
cold virusadenovirus. It is a poster child for translational